Mechanisms That Regulate the Function of the Selectins and Their Ligands

Abstract

Selectins are a family of three cell adhesion molecules (L-, E-, and P-selectin) specialized in capturing leukocytes from the bloodstream to the blood vessel wall. This initial cell contact is followed by the selectin-mediated rolling of leukocytes on the endothelial cell surface. This represents the first step in a cascade of molecular interactions that lead to leukocyte extravasation, enabling the processes of lymphocyte recirculation and leukocyte migration into inflamed tissue. The central importance of the selectins in these processes has been well documented in vivo by the use of adhesion-blocking antibodies as well as by studies on selectin gene-deficient mice. This review focuses on the molecular mechanisms that regulate expression and function(s) of the selectins and their ligands. Cell-surface expression of the selectins is regulated by a variety of different mechanisms. The selectins bind to carbohydrate structures on glycoproteins, glycolipids, and proteoglycans. Glycoproteins are the most likely candidates for physiologically relevant ligands. Only a few glycoproteins are appropriately glycosylated to allow strong binding to the selectins. Recently, more knowledge about the structure and the regulated expression of some of the carbohydrates on these ligands necessary for selectin binding has been accumulated. For at least one of these ligands, the physiological function is now well established. A novel and exciting aspect is the signaling function of the selectins and their ligands. Especially in the last two years, convincing data have been published supporting the idea that selectins and glycoprotein ligands of the selectins participate in the activation of leukocyte integrins.

CD99 Is a Key Mediator of the Transendothelial Migration of Neutrophils

“…To enter tissues, neutrophils (polymorphonuclear cells (PMN)) 3 must traverse the endothelial barrier, usually in a paracellular manner across endothelial cell (EC) borders (1,2). Exit of neutrophils and other leukocytes from vascular flow is a multistep process that begins with rolling of the leukocyte along the EC wall via interactions between selectins (CD62E, L, and P) and their sialylated receptors (3)(4)(5). The captured leukocytes interact with chemokines or other agents presented on the apical surface of the endothelium, which activate leukocyte ␤ 1 and ␤ 2 integrins (LFA-1, Mac-1, and VLA-4) to bind tightly to their ligands (ICAM-1, ICAM-2, and VCAM-1) (6 -9).…”

SELPLG Gene Polymorphisms in Relation to Plasma SELPLG Levels and Coronary Artery Disease

“…The interaction between leukocytes and endothelium wall/platelets not only requires the presence of P-selectin, but also of a counterligand on the leukocyte surface. Among the various P-selectin ligands already described (Vestweber & Blanks, 1999), the P-selectin glycoprotein ligand-1 (SELPLG/CD162) seems to be the major one mediating leukocyte recruitment to platelets and the endothelium (Kansas, 1996;Norman et al 1995). SELPLG is a dimeric mucinlike glycoprotein expressed on all leukocyte surfaces, constituted by two monomers of molecular mass of ∼ 120-kDa (Moore et al 1992).…”

Fucosyltransferase VII-Deficient Mice with Defective E-, P-, and L-Selectin Ligands Show Impaired CD4+ and CD8+ T Cell Migration into the Skin, but Normal Extravasation into Visceral Organs

“…The selectin family consists of three closely related cell surface molecules, E-selectin (CD62E), P-selectin (CD62P), and L-selectin (CD62L). The Eand P-selectins are expressed on activated vascular endothelium, and interact with their receptors on granulocytes, monocytes, and activated T cells (3). L-selectin is constitutively expressed on most leukocytes and plays an important role in leukocyte homing into lymphoid tissue.…”

“…L-selectin binds to at least four different glycosylated ligands expressed by high endothelial venules of lymph nodes, including glycosylated cell adhesion molecule-1, CD34, mucosal addressin cell adhesion molecule-1, and sulfated glycoprotein 200 (4). L-selectin also binds P-selectin glycoprotein ligand-1 (PSGL-1) 3 on leukocytes (5)(6)(7)(8).…”